ULK1 confers neuroprotection by regulating microglial/macrophages activation after ischemic stroke.

Microglial activation and autophagy play a critical role in the progression of ischemic stroke and contribute to the regulation of neuroinflammation. Unc-51-like kinase 1 (ULK1) is the primary autophagy kinase involved in autophagosome formation. However, the impact of ULK1 on neuroprotection and microglial activation after ischemic stroke remains unclear. In this study, we established a photothrombotic stroke model, and administered SBI-0206965 (SBI), an ULK1 inhibitor, and LYN-1604 hydrochloride (LYN), an ULK1 agonist, to modulate ULK1 activity in vivo. We assessed sensorimotor deficits, neuronal apoptosis, and microglial/macrophage activation to evaluate the neurofunctional outcome. Immunofluorescence results revealed ULK1 was primarily localized in the microglia of the infarct area following ischemia. Upregulating ULK1 through LYN treatment significantly reduced infarct volume, improved motor function, promoted the increase of anti-inflammatory microglia. In conclusion, ULK1 facilitated neuronal repair and promoted the formation of anti-inflammatory microglia pathway after ischemic injury.

Neuregulin-1/PI3K signaling effects on oligodendrocyte proliferation, remyelination and behaviors deficit in a male mouse model of ischemic stroke.

In this study, we investigated the effect of neuregulin-1 (NRG1) on demyelination and neurological function in an ischemic stroke model, and further explored its neuroprotective mechanisms. Adult male ICR mice underwent photothrombotic ischemia surgery and were injected with NRG1 beginning 30 min after ischemia. Cylinder and grid walking tests were performed to evaluate the forepaw function. In addition, the effect of NRG1 on neuronal damage/death (Cresyl violet, CV), neuronal nuclei (NeuN), nestin, doublecortin (DCX), myelin basic protein (MBP), non-phosphorylated neurofilaments (SMI-32), adenomatous polyposis coli (APC), erythroblastic leukemia viral oncogene homolog (ErbB) 2, 4 and serine-threonine protein kinase (Akt) in cortex were evaluated using immunohistochemistry, immunofluorescence and western blot. The cylinder and grid walking tests exposed that treatment of NRG1 observably regained the forepaw function. NRG1 treatment reduced cerebral infarction, restored forepaw function, promoted proliferation and differentiation of neuron and increased oligodendrogliogenesis. The neuroprotective effect of NRG1 is involved in its activation of PI3K/Akt signaling pathway via ErbB2, as shown by the suppression of the effect of NRG1 by the PI3K inhibitor LY294002. Our results demonstrate that NRG1 is effective in ameliorating the both acute phase neuroprotection and long-term neurological functions via resumption of neuronal proliferation and differentiation and oligodendrogliogenesis in a male mouse model of ischemic stroke.